Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can ameliorate high-fat diet or western-diet induced experimental Non-alcoholic steatohepatitis (NASH). However, its functional implications in the methionine-choline dietary model, remain incompletely understood. Here, we investigated the physiological relevance of gut microbiota in methionine-choline deficient (MCD) diet induced NASH. Experimental liver disease was induced by 8 weeks of MCD feeding in wild-type (WT) mice, either with or without commensal microbiota depletion, by continuous broad-spectrum antibiotic (AB) treatment. MCD diet induced steatohepatitis was accompanied by a reduced gut microbiota diversity, indicating intestinal dysbiosis. MCD treatment prompted macroscopic shortening of the intestine, as well as intestinal villi in histology. However, gut microbiota composition of MCD-treated mice, neither resembled human NASH, nor did it augment the intestinal barrier integrity or intestinal inflammation. In the MCD model, AB treatment resulted in increased steatohepatitis activity, compared to microbiota proficient control mice. This phenotype was driven by pronounced neutrophil infiltration, while AB treatment only slightly increased monocyte-derived macrophages (MoMF) abundance. Our data demonstrated the differential role of gut microbiota, during steatohepatitis development. In the context of MCD induced steatohepatitis, commensal microbiota was found to be hepatoprotective.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western societies and due to the obesity epidemic the incidence keeps rising [1,2,3]
Non-alcoholic Steatohepatitis (NASH) is a disease characterized by hepatic steatosis and inflammation, which can further progress to fibrosis and hepatocellular carcinoma (HCC) [1,25]
Over- and malnutrition is widely accepted as the main cause of non-alcoholic steatohepatitis (NASH)—not all obese Patients develop NASH and at the same time there are lean patients suffering from active NASH [27]
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western societies and due to the obesity epidemic the incidence keeps rising [1,2,3]. The term NAFLD covers a spectrum of disease manifestations ranging from liver steatosis over non-alcoholic steatohepatitis (NASH), liver fibrosis, to advanced disease states, such as cirrhosis and hepatocellular carcinoma (HCC) [2]. Western sedentary lifestyle and high caloric diets are the strongest and most significant risk factors for NAFLD development [4]. 90% of obese patients are affected by hepatic steatosis, which usually remains clinically asymptomatic. Thirty percent of patients diagnosed with NAFLD demonstrate histological signs of inflammation, which causes liver cell damage and fuels disease progression towards liver fibrosis and more advanced states, such as cirrhosis and HCC [5]. Given the pivotal role of hepatic inflammation as a mediator of disease phase transition towards irreversible cirrhosis and HCC, understanding the underlying mechanisms that perpetuate the inflammatory response in the liver seems key, in order to design novel disease-modifying therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
